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Case Reports  |   December 1997
Susceptibility to Malignant Hyperthermia Manifested as Delayed Return of Increased Serum Creatine Kinase Activity and Episodic Rhabdomyolysis after Exercise 
Author Notes
  • (Kojima) Department of Anesthesiology, Suwa Red Cross Hospital.
  • (Oku) Surgical Center, Hospital of Shiga University of Medical Science.
  • (Takahashi) Department of Anesthesiology, Shiga University of Medical Science.
  • (Mukaida) Department of Anesthesiology and Resuscitology, Hiroshima University School of Medicine.
  • Received from the Department of Anesthesiology, Suwa Red Cross Hospital, Nagano, Japan. Submitted for publication April 3, 1997. Accepted for publication July 31, 1997. Presented at the 20th annual meeting for the study of malignant hyperthermia in Tokyo, Japan, November 23, 1996. A part of this case was also reported at the 16th annual meeting of the Japan Society for Clinical Anesthesia in Tokyo, Japan, November 6–8, 1996.
  • Address reprint requests to Dr. Kojima: Department of Anesthesiology, Suwa Red Cross Hospital. 19–5 Kowata, Suwa-shi, Nagano, 392 Japan. Address electronic mail to: cnc16799@chunichi-net.or.jp.
Article Information
Case Reports
Case Reports   |   December 1997
Susceptibility to Malignant Hyperthermia Manifested as Delayed Return of Increased Serum Creatine Kinase Activity and Episodic Rhabdomyolysis after Exercise 
Anesthesiology 12 1997, Vol.87, 1565-1567. doi:
Anesthesiology 12 1997, Vol.87, 1565-1567. doi:
It is difficult to definitely predict the occurrence of malignant hyperthermia (MH) and to identify patients at risk before anesthesia. Preoperative increase of serum creatine kinase activity (CK) at rest is considered one of the risk factors for MH susceptibility. [1 ] However, the use of CK determination as a screening test for malignant hyperthermia susceptibility (MHS) has failed in some patients. [2,3 ] We present a case of a patients with MHS with normal resting CK level who showed asymptomatic delayed recovery of exercise-induced CK elevation.
Case Report 
A 28-yr-old, 79-kg muscular man, who was scheduled for excision of herniated lumbar disc during general anesthesia, demonstrated increased serum CK level of 3,794 U/l (normal, 45–195 U/l) with an MM type of 99% on the day of admission. The CK had been 185 U/l before an uneventful appendectomy with spinal analgesia 9 months earlier. The present surgery was postponed, and serial serum CK values decreased daily, but it took 17 days to return to the normal range. During that period, examinations by the neurologists failed to reveal myositis or apparent neuromuscular diseases. There was neither remarkable medical history nor family history of MH or any muscular disease. However, the patient was sometimes aware of muscle cramps and dark-colored urine after exercise. He ran a 20-km race 23 days before admission to the hospital and had not been exercising since the race because low back pain had developed. This was later diagnosed as one of the symptoms of herniated disc. That race was presumed to be the cause of his high CK values his, delayed recovery of CK, and the episodes of rhabdomyolysis suggested underlying muscular disease. Diagnostic muscle biopsy from the quadriceps femoris muscle was obtained for caffeine-halothane contracture test (CHCT), calcium-induced calcium release (CICR) test, and histopathologie examination.
Histopathologic study showed no specific changes such as central core disease or other neuromuscular diseases, but a mild myopathy was recognized. The patient was diagnosed as having MHS based on CHCT according to the protocol of the European Malignant Hyperthermia Group [4 ](the threshold concentrations of caffeine and halothane for 0.2-g increase of tension were 2 mM and 1%, respectively) and that of the North American Malignant Hyperthermia Group [5 ](0.4-g and 1.2-g contracture on exposure to 2 mM caffeine and 3% halothane, respectively). CICR rate was not accelerated. [6 ] Phosphorus-31 nuclear magnetic resonance (sup 31 P NMR) spectroscopy [7 ] demonstrated a greater decrease and slower recovery in forearm muscle pH after exercise and an early depletion of phosphocreatine during the exercise compared with a control subject confirmed as MH negative by CHCT (Figure 1).
Figure 1. Serial changes of phosphocreatine peak area (Pcr: shown as the ratio to the preexercise value) and intracellular pH (pHi) in the patient ([square bullet, filled]) and the control subject ([circle, open]) assessed by31P-NMR spectroscopy. The test was performed according to the method reported by Olgin J et al. [7 ]
Figure 1. Serial changes of phosphocreatine peak area (Pcr: shown as the ratio to the preexercise value) and intracellular pH (pHi) in the patient ([square bullet, filled]) and the control subject ([circle, open]) assessed by31P-NMR spectroscopy. The test was performed according to the method reported by Olgin J et al. [7]
Figure 1. Serial changes of phosphocreatine peak area (Pcr: shown as the ratio to the preexercise value) and intracellular pH (pHi) in the patient ([square bullet, filled]) and the control subject ([circle, open]) assessed by31P-NMR spectroscopy. The test was performed according to the method reported by Olgin J et al. [7 ]
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Surgery was uneventfully performed during spinal analgesia 3 months later. The CK levels peaked at 391 U/l on the following day and normalized in 3 days.
Discussion 
Even in a healthy person, gross increases in serum CK level after high-intensity or prolonged weight-bearing exercises, such as a marathon, have been reported. [8 ] However, considering that CK levels generally normalize in 3–7 days, it would be assumed that if serum CK activity exceeds 10,000 U/l after the exercise or 5,000 U/l more than 24 h after the event, subclinical myopathy predisposing the person to the risk of rhabdomyolysis was likely to be present. [8,9 ] Our patient showed a serum CK level of more than 3,000 U/l 23 days after a 20-km run, suggesting the presence of subclinical myopathy.
Subclinical myopathy is often related to MH. Although the primary defect in MH patients lies in the sarcoplasmic reticulum of skeletal muscle cells, histologic examination cannot detect any specific findings of MH with a few exceptions, such as patients with central core disease or King-Denborough syndrome. [10 ] Pathophysiologically, MH may be regarded as a subclinical primary myopathy with secondary systemic changes. [11 ] Epidemiologic studies show that many MHS patients have episodes of muscular cramps, pain, and pyrexia after exercise, [12 ] which suggests that these patients are associated with an underlying myopathy. Sporadically reported MHS subjects linked with exercise-induced myolysis [13,14 ] support this idea. Allsop et al. also showed that MHS subjects showed decreased power output and suggested the presence of an underlying myopathy manifested by high-intensity exercise in MHS patients. [15 ]
This patient was diagnosed as MHS by CHCT. However, a functioning abnormality in the ryanodine receptor of the sarcoplasmic reticulum could not be identified as the cause of MHS because CICR was not accelerated. The mechanism of persistent increased CK values after the semi-marathon suggests increased leakage of CK through the muscle cell membrane caused by the loss of membrane integrity maintained by high energy compounds such as phosphocreatine and ATP, which might be the explanation for the patient's episodic rhabdomyolysis. Early depletion and slow recovery of such high energy compounds during and after muscle-loading exercise, which occurs when the production of ATP via metabolic pathway is deteriorated or when the breakdown of ATP is accelerated, might play a role in disturbing the function of the muscle cell membrane.
We conclude that delayed recovery of CK level increase after prolonged weight-bearing exercise in this patient represents an underlying myopathy that might be associated with MHS. We should not overlook the possibility of MHS in an otherwise healthy person showing an abnormal CK increase after exercise.
References 
References 
Larach MG, Localio AR, Allen GC, Denborough MA, Ellis FR, Gronert GA, Kaplan RF, Muldoon SM, Nelson TE, Ording H, Rosenberg H, Waud BE, Wedel DJ: A clinical grading scale to predict malignant hyperthermia susceptibility. Anesthesiology 1994; 80:771-9.
Ording H: Diagnosis of susceptibility to malignant hyperthermia in man. Br J Anaesth 1988; 60:287-302.
Paasuke Rein T, Keith A, Brownell W: Serum creatine kinase level as a screening test for susceptibility to malignant hyperthermia. JAMA 1986; 255:769-71.
The European Malignant Hyperpyrexia Group: A protocol for the investigation of malignant hyperpyrexia (MH) susceptibility. Br J Anaesth 1984; 56:1267-9.
Larach MG for the North American Malignant Hyperthermia Group: Standardization of the caffeine halothane muscle contracture test. Anaesth Analg 1989; 69:511-5.
Endo M, Yagi S, Ishizuka T, Horiuchi K, Koga Y, Amaha K: Changes in the Ca-induced Ca release mechanism in the sarcoplasmic reticulum of the muscle from a patient with malignant hyperthermia. Biomed Res 1983; 4:83-92.
Olgin J, Argov Z, Rosenberg H, Tuchler M, Chance B: Non-invasive evaluation of malignant hyperthermia susceptibility with phosphorus nuclear magnetic resonance spectroscopy. Anesthesiology 1988; 68:507-13.
Hortobagyi T, Denahan T: Variability in creatine kinase: Methodological, exercise and clinically related factors. Int J Sports Med 1989; 10:69-80.
Noakes TD: Effect of exercise on serum enzyme activities in humans. Sports Med 1987; 4:245-67.
Figarella Branger D, Pellissier JF: Malignant hyperthermia myopathy, Malignant Hyperthermias. Edited by Aubert M, Borsarelli J, Kambatta HJ, Kozak Ribben G. NorMED Verlag. Bad Humburg Englewood, Madrid, 1993, pp 27-37.
Gronert GA, Mott M, Lee J: Aetiology of malignant hyperthermia. Br J Anaesth 1988; 60:253-67.
Smith RJ: Preoperative assessment of risk factors. Br J Anaesth 1988; 60:317-9.
Hackl W, Winkler M, Mauritz W, Sporn P, Steinbereithner K: Muscle biopsy for diagnosis of malignant hyperthermia susceptibility in two patients with severe exercise-induced myolysis. Br J Anaesth 1991; 66:138-40.
Kozak Ribbens G, Rodet L, Borsarelli J, Aubert M, Cozzone PJ: Exercise and malignant hyperthermia: Family investigations. Br J Anaesth 1993; 70:A92.
Allsop P, Jorfeldt L, Rutberg H, Lennmarken C, Hall GM: Delayed recovery of muscle pH after short duration, high intensity exercise in malignant hyperthermia susceptible subjects. Br J Anaesth 1991; 66:541-5.
Figure 1. Serial changes of phosphocreatine peak area (Pcr: shown as the ratio to the preexercise value) and intracellular pH (pHi) in the patient ([square bullet, filled]) and the control subject ([circle, open]) assessed by31P-NMR spectroscopy. The test was performed according to the method reported by Olgin J et al. [7 ]
Figure 1. Serial changes of phosphocreatine peak area (Pcr: shown as the ratio to the preexercise value) and intracellular pH (pHi) in the patient ([square bullet, filled]) and the control subject ([circle, open]) assessed by31P-NMR spectroscopy. The test was performed according to the method reported by Olgin J et al. [7]
Figure 1. Serial changes of phosphocreatine peak area (Pcr: shown as the ratio to the preexercise value) and intracellular pH (pHi) in the patient ([square bullet, filled]) and the control subject ([circle, open]) assessed by31P-NMR spectroscopy. The test was performed according to the method reported by Olgin J et al. [7 ]
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